Maria A. Chiacchio

Synthesis and Biological Activity of Phosphonated Nucleosides: Part 1Furanose, Carbocyclic and Heterocyclic Analogues

Phosphonated nucleosides represent a promising alternative in the improvement of the biological activity of nucleoside analogues in antiviral and anticancer chemotherapy. The basic concept, the chemistry, the different structural modifications and their effects on the antiviral potency will be discussed in this review.

Antiviral activity of seed extract from Citrus bergamia towards human retroviruses

The effects of an extract from Citrus bergamia (BSext) and those of two products purified from the same extract, that is, nomilin and limonin, and reference compounds, towards HTLV-1 have been reported. Moreover, they were also compared with those obtained towards HIV-1. Results showed that the efficacy of both BSext and limonin in inhibiting HTLV-1 as well as HIV-1 expression in infected cells, as evaluated by comparable quantitative assays, was close to that of the effective, reference compounds, respectively. The protective effect of BSext and of the purified products was associated with the inhibition of both HTLV-1 and HIV-1 RT activities in conceptually similar, cell-free assays. The cytotoxicity of the assayed compounds of natural origin was substantially less pronounced than that of the reference compounds, thus showing a favourable selectivity index for the novel BSext product.

Copper(II)-Catalyzed Alkoxyhalogenation of Alkynyl Ureas and Amides as a Route to Haloalkylidene-Substituted Heterocycles.

A highly effective synthesis of haloalkylidene-substituted heterocycles by copper(II)-catalyzed cyclization of alkynyl ureas and secondary amides has been developed. The reaction, which involves a catalytic amount of CuCl2 and a stoichiometric amount of N-halosuccinimide, occurs selectively through an alkoxyhalogenation process. Alternatively, alkoxychlorination and alkoxybromination reactions can be performed working solely with stoichiometric CuCl2 and CuBr2, respectively.

C-5’-Triazolyl-2’-oxa-3’-aza-4’a-carbanucleosides: Synthesis and biological evaluation

Summary A novel series of 2’-oxa-3’-aza-4’a-carbanucleosides, featured with a triazole linker at the 5’-position, has been developed by exploiting a click chemistry reaction of 5’-azido-2’-oxa-3’-aza-4’a-carbanucleosides with substituted alkynes. Biological tests indicate an antitumor activity for the synthesized compounds: most of them inhibit cell proliferation of Vero, BS-C-1, HEp-2, MDCK, and HFF cells with a CC50 in the range of 5.0–40 μM. The synthesized compounds do not show any antiviral activity.

Synthesis and biological evaluation of furopyrimidine N,O-nucleosides

A series of modified N,O-nucleosides, characterized by the presence of a furopyrimidine moiety, has been synthesized by exploiting a Sonogashira cross coupling reaction of 1-isoxazolidinyl-5-iodouracil with alkynes, followed by treatment with CuI in refluxing TEA/MeOH mixture. The obtained compounds were screened against both RNA and DNA viruses. None of the compounds were endowed with antiviral activity at subtoxic concentrations. However, some of them were able to inhibit proliferation of MRC-5, Vero, BS-C-1 cells by 50% (CC50) at concentrations ranging from 0.7 to 62.5 mM.

Computational Mechanistic Study of Thionation of Carbonyl Compounds with Lawesson’s Reagent

The thionation reaction of carbonyl compounds with Lawessons reagent (LR) has been studied using density functional theory methods and topological analyses. After dissociation of LR, the reaction takes place through a two-step mechanism involving (i) a concerted cycloaddition between one monomer and the carbonyl compound to form a four-membered intermediate and (ii) a cycloreversion leading to the thiocarbonyl derivative and phenyl(thioxo)phosphine oxide. Topological analyses confirmed the concertedness and asynchronicity of the process. The second step is the rate-limiting one, and the whole process resembles the currently accepted mechanism for the lithium salt-free Wittig reaction. No zwitterionic intermediates are formed during the reaction, although stabilizing electrostatic interactions are present in initial stages. Phenyl(thioxo)phosphine oxide formed in the thionation reaction is capable of performing a second thionation, although with energy barriers higher than the first one. The driving force of the thionation reactions is the formation of trimers from the resulting monomers. In agreement with experimental observations, the amides are the most reactive when compared with esters, aldehydes, and ketones and the reaction is slightly influenced by the polarity of the solvent. Whereas for amides and esters substituents have little effect, aldehydes and ketones are influenced by both steric and electronic effects.

Ab initio MP2 and density functional theory computational study of AcAlaNH2 peptide hydration: a bottom-up approach.

AcAlaNH2 ⋅ n H2O (n=1-13) complexes have been proposed as models to account for water solvent effects on the molecular properties of N-acetyl-L-alanine amide. Ab initio computations are planned to evaluate peptide-water interactions and to provide a means for approximating relative effects of the short-range many-body interactions arising in real solution without introducing any external parameters intended to quantify empirical or semiempirical potential-energy functions. The present bottom-up approach reveals the formation of compact ring clusters of water molecules strongly bonded to peptidic polar groups throughout hydrogen bonds. The explicit coordination of water molecules around the peptide renders the fully extended (FE) and polyproline II (PPII) conformers more stable with respect to the 310 helix or γ turn. The alternance of donor and acceptor groups on both sides of the FE and PPII conformers allows for synergy and extensive H-bonding.

Synthesis and biological activity of new arenediyne-linked isoxazolidines

Arenediyne-isoxazolidine conjugates have been synthesized as a new scaffold for the development of bioactive mimics. Some of the synthesized compounds are endowed with antiproliferative activity against three human cancer cell lines. Their thermal reactivity suggests that the biological activity probably could not be linked to the Bergman cyclization.

Synthesis and Biological Properties of 5-(1H-1,2,3-Triazol-4-yl)isoxazolidines: A New Class of C-Nucleosides

A novel series of C-nucleosides, featuring the presence of a 1,2,3-triazole ring linked to an isoxazolidine system, has been designed as mimetics of the pyrimidine nucleobases. An antiproliferative effect was observed for compounds 17a and 17b: the growth inhibitory effect reaches the 50% in HepG2 and HT-29 cells and increases up to 56% in the SH-SY5Y cell line after 72 h of incubation at a 100 µM concentration.

Introducing topology to assess the synchronicity of organic reactions. Dual reactivity of oximes with alkenes as a case study

The synchronicity of organic reactions not always can be determined by only the analysis of transition structures. We present a case study that illustrates that topological analyses provide information regarding synchronicity that, often, is not reflected in the geometry of transition structures. We have chosen the competitive reactions of oximes with alkenes, (3 + 2) dipolar cycloaddition and ene-like reaction, which have been computationally studied to determine the parameters favoring each process. The competition between the two reactions is particularly evidenced in alkenyl oximes leading to intramolecular processes. Up to 26 examples of intramolecular reactions have been calculated and the results predicted the favored process.